Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
  • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

• This invention relates to optically active 3,4-­dihydrobenzoxazine derivatives and to a process for pre­paring the same useful as intermediates for preparing excellent antibacterial agents.
• Ofloxacin has an asymmetric carbon atom at the 3-­position and is obtained as a racemic mixture.
• the 3S-methyl compound (IS) which is represented by the following formula was confirmed to have higher activity and reduced toxicity in comparison with the racemic compound or 3R-methyl compound (IR).
• An object of this invention is to provide optically active isomers of 3-alkyl-3,4-dihydro-2H-[1,4]benzoxazine derivatives represented by the formula (III) wherein X1, X2 and X3, which may be the same or different, each represents a hydrogen atom or a halogen atom, and R1 represents an alkyl group having 1 to 6 carbon atoms, and the salts thereof.
• Another object of this invention is to provide novel intermediates represented by formula (II) below which are useful for synthesizing optically active 3-alkyl-3,4-­dihydro-2H-[1,4]benzoxazine derivatives with chiral reducing agents.
• a further object of this invention is to provide a process for preparing optically active isomers of 3,4-­dihydro-2H-[1,4]benzoxazine derivatives (III) shown above by asymmetric reduction of 2H-[1,4]benzoxazine derivatives (II) shown below with chiral reducing agents.
• the 3S-isomer of Ofloxacin and its analogs are preferable.
• the synthesis of compound (IS) and its analogues is best achieved by starting from the optically active compound (IIIS).
• This optically active compound (IIIS) is easily prepared by asymmetric reduction of compound (II) using chiral reducing agents.
• Suitable chiral reducing agents include a number of different re­agents applicable for the present invention, e.g., chiral complex of borohydrides or aluminum hydrides, and chiral complex of metal catalysts.
• Such complexes are exemplified as follows: chiral acyloxy borohydries (as disclosed in T. Iwakuma et al., Chem. Pharm. Bull.
• the reagent is represented by the following formula: MBH 4-n (RCOO) n wherein M represents an alkali metal such as lithium, sodium and potassium; and n represents an integer of from 1 to 3; and RCOO represents an acyloxy residue such as an acetoxy, a propionyloxy, a chloroacetoxy, or a benzoyloxy residue or a residue represented by the following formula: wherein R2 and R3, which may be the same or different, each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an isopropyl group, or an aralkyl group, for example, an unsub­stituted or substituted phenylalkyl group having from 1 to 3 carbon atoms in the alkyl moiety thereof, such as a benzyl group, or substituted benzyl group; or R2 and R3 may combine and represent a methylene chain such as -(CH
• (S)-amino acid especially N-acyl-(S)-proline
• These chiral acyloxy borohydrides are easily prepared from alkali metal borohydride and N-acyl-(S)-proline in tetrahydrofuran as reported by Iwakuma et al. ( J. Synth. Org. Chem., Japan , 41 , 453 (1983); Chem. Pharm. Bull. , 31 , 70 (1983)).
• n which means a number of the acyloxy residue in the reducing agent is in the range of 1 to 3, and is preferably 3 for the higher optical purity of the reduced product as reported in literature references.
• the molar ratio of 2H-benzoxazine derivative (II) and the reducing agent is in the range of from 1:1 to 1:5, preferably 1:2.5.
• the reduction with the chiral acyloxy borohydrides may be carried out in a solvent inert to the reaction, such as diethyl ether, 1,2-dimethoxyethane, acetonitrile, tolu­ene, ethyl acetate, 1,1,2,2-tetrachloroethane, 1,1,2,2-­tetrachloroethylene, 1,1-dichloroethane, 1,2-dichloroethane, dichloromethane and the like.
• solvents halogen-­containing solvents are preferred.
• the amount of the solvent can be in the range of from 5 to 50 parts by volume, and preferably in the range of from 5 to 20 parts by volume, to the amount of the benzoxazine derivative (II).
• the reduction can be performed by mixing a solution of an acyloxy borohydride and a solution of 2H-benzoxazine in a solvent mentioned above.
• the chirality of the resulting reduction product corresponds to that of the ligand of the reducing agent used. That is, when acyloxy borohydride derived from S-amino acid is used, the reduction product has S-configuration.
• optically pure 3,4-dihydrobenzoxazine is readily obtained from a crude mixture by a simple purification, e.g., recrystallization.
• the purification of a mixture in which one isomer is present in a larger amount than the other is much easier than a mixture containing an equal amount of the isomers.
• the reduction can be performed at a temperature in the range of from about -60°C to about 60°C, preferably from -45°C to 20°C, for a period of from about 10 minutes to about 48 hours.
• the end of the reaction can be detected by TLC.
• Tris[(S)-N-isobutyloxycarbonylpropyloxy]hydroborate was prepared from sodium borohydride and N-isobutyloxycar­bonyl-(S)-proline and a solution of 15.5 g of this hydride in 30 ml of anhydrous dichloromethane was cooled to -41°C. To this was added a solution of the imine (II) obtained above in 15 ml of anhydrous dichloromethane was added under a nitrogen atmosphere (at the end of the addition, the internal temperature raised to -34°C).
• % ee is an abreviation for % enantiomer excess, and is a measure of an optical purity of an optically active compound (see, for example, Asymmetric Synthesis , Vol. 1, p. 45, 60, Academic Press, New York (1983), edited by J.D. Morrison et al.).
• the % ee is cal­ culated as follows. wherein [R] represents a molar ratio of one isomer in percent, and [S] represents that of the other isomer, when [R]+[S] is taken as 100%.
• the collected yellow powder was suspended in 5 ml of 95% methanol and to this was added 1 ml of triethylamine. The mixture was heated under reflux for 25 hours. The solvent was removed under reduced pressure and the residue was dissolved in 10 ml of 10% hydrochloric acid. After this solution was extracted with chloroform three times, the aqueous layer was rendered basic to pH 11 using a sodium hydroxide aqueous solution. The pH of this solution was readjusted to 7.3 using 1N hydrochloric acid, and the solution was extracted with three 15 ml portions of chloroform. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1987
  • 1987-12-23 AT AT87119158T patent/ATE110061T1/de not_active IP Right Cessation
  • 1987-12-23 DE DE3750396T patent/DE3750396T2/de not_active Expired - Lifetime
  • 1987-12-23 EP EP87119158A patent/EP0273399B1/de not_active Expired - Lifetime
  • 1987-12-23 ES ES87119158T patent/ES2061481T3/es not_active Expired - Lifetime
  • 1987-12-24 KR KR1019870014904A patent/KR950012563B1/ko not_active IP Right Cessation
  • 1987-12-24 CA CA000555410A patent/CA1305705C/en not_active Expired - Lifetime
  • 1987-12-28 PH PH36310A patent/PH23992A/en unknown
  • 1987-12-28 US US07/138,117 patent/US4895944A/en not_active Expired - Lifetime

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